3-Aminoalcoxy-6-hydrazino pyridazines

ABSTRACT

The invention provides new N-substituted 3-aminoalcoxy-6hydrazinopyridazines which have a marked anti-hypertensive activity, and a LD50 much higher than that of the clinically used drug hydralazine. The compounds of the invention are prepared by reacting 3-aminoalcoxy-6-halogenopyridazines with hydrazine.

United States Patent Pifferi June 24, 1975 4] 3-AMlNOALCOXY-6-HYDRAZINO 3,579,5l7 5/1971 Houlihan et al. 260/250 A PYRIDAZINES 3,598.822 8/1971 Anderson et al. 260/250 A 75 Inventor: Giorgio Panel-1, Milan, Italy THER PUBLICATIONS 73 Assignee: I S. F SJLA" Milan Italy Edgar A. StGCk Cl. 8]., J. Am. Chem. SOC., VOL 76,

4454-57, 1954 [22] Filed: Jan. 17, 1972 [2l] Appl, No; 218,531 Primary Examiner-Donald G. Daus Assistant Examiner-Jose Tovar Attorney, Agent, or Firm-Harold L. Stowell; Dennis [30] Foreign Application Priority Data Clarke May 29, 1971 Italy 25230/7l T [52] U.S. Cl... 260/250 A; 260/2475 D; 260/268 H; [57} ABS RACT 424/250 The Invention provldes new N-substituted 3-am1n0al- 51 1m. (:1 1. C07d 51/04 COXY-6-hydrazinopyridazines which have a marked 158 1 Field of Search 260/250 A ti-hypeflensive activity, and a 5 much higher than that of the clinically used drug hydralazine. The com- 5 References Cited pounds of the invention are prepared by reacting 3 UNITED STATES PATENTS aminoalcoxy-6-hal0genopyridazines with hydrazine.

2.858.311 10/1958 Steck 260/250 A 4 C a ms. No Drawings 3-AMINOALCOXY-6-HYDRAZINO PYRIDAZINES This invention relates to compounds having antihypertensive activity. and to their preparation.

These results show that the compounds of this invention are less toxic and more active than hydralazine. in both tests and for both the animal species tested.

This invention therefore includes within its scope It is known that some o-substituted B-hydrazino- 5 pharmaceutical compositions containing as an active pyridazines have. in addition to a marked antiprinciple one or more compounds of formula (I) or hypertensive activity. also an appreciable toxicity their non-toxic salts with organic or inorganic acids. in which limits their usefulness. especially when they are association with a compatible pharmaceutical vehicle. used for a long time. as frequently necessary in the According to this invention. the compounds of fortreatment of hypertension. l0 mula (I) are prepared by reacting compounds of the The invention provides N-substituted 3-aminoalcoxyformula: o-hydrazinopyridazines which have a marked antihypertensive activity and a LD much higher than that of the clinically used drug hydralazine. R

The new compounds of this invention are the N- substituted 3-aminoalcoxy-6-hydrazinopyridazines. of 2 fl 11 general formula: R

R NHHHZ r wherein R. R and are as defined above and X is chlo- )1 rine or bromine, with a hydrazme. wh|ch may be anhydrous or in the form of the monohydrate. The com- R pounds of formula (II) are heated with hydrazine to a 1 2 temperature from 20C to the boiling point of the mix- 5 ture. preferably between 70 and l l5C. The reaction wherein n is an integer from 2 to 6, R is hydrogen. can be conducted using an excess ofhydrazine,or using lower alkyl. or lower hydroxyalkyl. R is lower alkyl. an inert organic solvent, such as ethanol. propanol. or lower hydroxyalkyl, or phenyl. or R and R together cyclohexanol. The excess of hydrazine is employed to with the nitrogen atom to which they are bound reprepromote the reaction, and to bind the hydrochloric or sent a heterocyclic ring having 1 or 2 heteroatoms, hydrobromic acid that forms during the reaction. preferably a 5- or 6 membered ring, e.g. pyrrolidino, The intermediates offormula (II) are easily prepared piperidino. morpholino, or 4-lower alkylpiperazino. by reacting 3.6-dichloropyridazine or 3.6- The compounds of formula (I) may be employed as dibromopyridazine with an aminoalcohol of formula: such or in the form ofacid addition salts, obtained from i I the bases by treatment with mineral acids, such as hydrochloric. hydrobromic. or sulfuric acid, or organic acids. such as acetic. succinic, benzoic. or p-toluene- N J 3 -UH sulfonic acid.

The hypotensive effect of the compounds of formula 40 3 (I) has been proved by administering them intrave- 1 nously in aqueous solution to anaesthetized cats and measuring the decrease in their arterial blood pressure. wherein R. R and n are as defined above. The reaction The antihypertensive action of the new compounds has can be accomplished. according to the nature of the been measured by inducing renal hypertension in rats aminoalcohol employed. either by heating the halogeby the method of Grollman (Proc. Soc. Exptl. Biol. and no-pyridazine with the compound of formula ([11) in Med.. 57. lO2. 1944) and observing the decrease in arthe presence of anhydrous sodium or potassium carterial blood pressure following oral administration of bonate in an aprotic high-boiling solvent, such as dian aqueous solution of a compound of the invention as methylformamide. or else by heating the a salt, e.g. the hydrochloride. halogenopyridazine with an anhydrous alkali metal salt The minimum effective dosages of certain comof the aminoalcohol of formula (ill) in an inert organic pounds of formula (I) in the two aforesaid tests and solvent, such as benzene or toluene. The reaction temtheir corresponding approximate intraperitoneal LD perature is not critical and may range from 50C to the in the rat are grouped in the following Table together boiling point of the selected solvent. The so obtained with the values for hydralazine. compounds of formula (I) are separated from the reac- TABLE Compound Mouse Anaesthetized Cat Awake hyperof tensive rat Example No. LD Effective Half Efi'ective dosage effect osage mg/kg mg/kg time: mg/kg intraperitoneal intravenous minutes orally 1 300 0.0! I20 0:5 2 800 0.2 150 3 900 0.1 130 Hydralazine 0.5 100 tion mixture and purified by conventional methods for organic bases.

The following Examples illustrate the invention.

EXAMPLE 1 3-( 2-Anilinoethoxy )-6-hydrazinopyridazine a. 3-(2-anilinoethoxyl-o-chloropyridazine 3.76 Grams of N-(Z-hydroxyethyl)-aniline and grams 2.98 of 3,6-dichloropyridazine are added to 40 ml of anhydrous dimethylformamide containing 10 grams of potassium carbonate and the mixture is heated to lC for hours with stirring. The insoluble mineral salts are filtered off, and the filtrate is concentrated to dryness under vacuum. The residue is taken up with chloroform, washed with water, dried over Na SO The solvent is removed by distillation and the remaining solid is recrystallized from ethyl acetate. 2.5 g (50% of theoretical) of 3-(2-anilinoethoxy)-6- chloropyridazine, m.p. 98l0lC. are obtained.

b. 3-(2-anilinoethoxy)-6-hydrazinopyridazine A mixture of 50 g of 3-(2-anilinoethoxy)-6- chloropyridazine in 500 ml of hydrazine monohydrate is refluxed for 3 hours. The reagent in excess is distilled off under vacuum and the residue is taken up with water and kept overnight in the refrigerator. The precipitate is collected by filtration and washed with warm ethanol. The residue is heated with an excess of boiling ethanol. the insoluble matter is filtered off over charcoal, and a solution of gaseous hydrogen chloride in diethyl ether is added to the filtrate, until the mixture is acid to Congo Red.

The precipitate is collected by vacuum filtration and recrystallized from ethanol, thus giving, in good yield, 3-(2-anilinoethoxy)-6-hydrazinopyridazine as the dihydrochloride. m.p. l89-l92C (dec). IR spectrum (Nujol): 3300-2000 (NH*), 1670 (SNH), 1610 (Pyridazine ring), 1590 and 1500 (phenyl), 1055 (CO), 760 cm (monosubstituted phenyl).

3-( 3 -Dimethylaminopropoxy--hydrazinopyridazine a. 3-(3-dimethylaminopropoxyl--chloropyridazine 9.2 Grams of sodium metal are finely subdivided in 140 ml of boiling anhydrous xylene, and 45.5 g of 3- dimethylaminopropanol are added to the heated mixture. When the sodium has entirely dissolved, the mixture is cooled to 60C, and a solution of 59.6 g of 3,6- dichloropyridazine in 100 ml of anhydrous xylene is added dropwise. After heating for [0 hours to 60C, the mixture is cooled and acidified with hydrochloric acid. The aqueous phase is separated and rendered alkaline while cold with a 30% aqueous sodium hydroxide solution. The oil that separates is extracted with diethyl ether. The extract is dried over anhydrous K CO and the solvent is removed by distillation. The residue is fractionally distilled under \acuum. thus gi\ing 60 g (70% of theoretical) of 3-1B-dimethylaminopropoxy)- b. 3-( 3-dimethylaminopropoxy l-fi hydrazinopyridazine 5 1 L4 Grams of 3-(B-dimethylaminopropoxy)-6- chloropyridazine are added to a solution of I00 ml of hydrazine monohydrate in 40 ml of ethanol. and the mixture is refluxed for 4 hours. The solution obtained is concentrated to dryness under a high vacuum. The residue is taken up with l50 ml of anhydrous methanol and acidified to Congo Red with a solution of gaseous hydrogen chloride in anhydrous methanol. The mixture is concentrated to approximately half its volume. and cooled, and the hydrazine dihydrochloride that separates is removed by filtration. The alcoholic filtrate is further concentrated and cooled, and the precipitate is collected by vacuum filtration. It is then purified by recrystallization from methanol, thus giving, in a good yield, 3-( 3-dimethylaminopropoxy )-6- hydrazinopyridazine dihydrochloride, m.p. 2l0212C (dec). IR spectrum (Nujol): 3300-2000 (NHU. l675 (SNH), 1625 (pyridazine ring), I030 cm (CO).

Analysis: Calculated for C,,H,;N,-,O.2HC1: C 38.00; H 6.74

N 24.92; Cl 24.62 7 Found: c 37.34; H 6.88;

N 24.60; Cl 24.82 a

EXAMPLES 3 5 The following compounds are prepared by operating as in Example 2:

3. 3-(2-diethylaminoethoxy)-6-hydrazinopyridazone dihydrochloride, m.p. 201203C (dec).

4. 3-(2-morpholinoethoxy)-6-hydrazinopyridazine dihydrochloride, m.p. 2152l8C (dec).

5. 3-(2-N-methylpiperazinoethoxy)-6- hydrazinopyridazine trihydrochloride, m.p. l65l68C (dec).

What we claim is:

l. A compound of the formula:

NHNH z or its pharmaceutically acceptable acid addition salts. i i l 

1. A COMPOUND OF THE FORMULA:
 2. 3-(2-Anilinoethoxy)-6-hydrazinopyridazine or its pharmaceutically acceptable acid addition salts.
 3. 3-(3-Dimethylaminopropoxy)-6-hydrazinopyridazine or its pharmaceutically acceptable acid addition salts.
 4. 3-(2-Diethylaminoethoxy)-6-hydrazinopyridazine or its pharmaceutically acceptable acid addition salts. 